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Morin hydrate attenuates S taphylococcus aureus virulence by inhibiting the self‐assembly of α‐hemolysin
Author(s) -
Wang J.,
Zhou X.,
Liu S.,
Li G.,
Shi L.,
Dong J.,
Li W.,
Deng X.,
Niu X.
Publication year - 2015
Publication title -
journal of applied microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.889
H-Index - 156
eISSN - 1365-2672
pISSN - 1364-5072
DOI - 10.1111/jam.12743
Subject(s) - zoonosis , christian ministry , china , veterinary medicine , medicine , political science , law
Aims To investigate the mechanism by which morin hydrate inhibits the haemolytic activity of α‐hemolysin (Hla), a channel‐forming toxin that is important for the pathogenesis of disease in experimental animals, and its therapeutic effect against Staphylococcus aureus pneumonia in a mouse model. Methods and Results The results from the in vitro (haemolysis, western blot and cytotoxicity assays) and in vivo (mouse model of intranasal lung infection) experiments indicated that morin hydrate, a natural compound with little anti‐ Staph. aureus activity, could effectively antagonize the cytolytic activity of Hla, alleviate human lung cell injury, and protect against mortality of Staph. aureus pneumonia in a mouse model of infection. Molecular dynamics simulations, free energy calculations and mutagenesis assays were further employed to determine the catalytic mechanism of inhibition, which indicated that a direct binding of morin to the ‘Stem’ domain of Hla (residues I107 and T109) and the concomitant change in conformation led to the inhibition of the self‐assembly of the heptameric transmembrane pore, thus inhibiting the biological activity of Hla for cell lysis. Conclusions Morin inhibited Staph. aureus virulence via inhibiting the haemolytic activity of α‐hemolysin. Significance and Impact of the Study These findings suggested that morin is a promising candidate for the development of anti‐virulence therapeutic agents for the treatment of Staph. aureus infections.